Although little is known about malaria immunity, the accepted Malaria Immunity Paradigm (MIP) is that resistance requires years of closely spaced infections to develop, frequent infections to maintain, and can be compromised by parasite antigenic diversity. The MIP was developed from studies in high P. falciparum transmission regions, but, in such settings, a myriad of factors drive the outcomes. Our proposed study presents an opportunity to test the MIP. P. vivax and P. falciparum emerged only 10 years ago in Iquitos, Peru. Now, there is 0.06 P. falciparum and 0.15 P. vivax infections/person/month during the transmission months of January-July. With our prospective longitudinal sampling for the past two years we have established that asymptomatic infections and even infections that are self-limited occur. From this and data from other low transmission regions, we present the novel alternative that low density and widely spaced P. falciparum infections are sufficient to develop and maintain immunity to a variety of different P. falciparum genetic types. We call this our Spaced Infection Dependent Malaria Immunity Hypothesis (SIDMI).We will challenge the MIP by determining if individuals who have <2 P. falciparum infections/year also have asymptomatic and self-limited infections, controlling for heterogeneity in infection, nutrition and P. vivax and malaria drug consumption (AIM1). To test our SIDMI hypothesis, we will determine how the resistance is related to successive P. falciparum and P. vivax infections and antibody response development (AIM2). We will test if resistance to P. falciparum is specific to particular genotype (strains), using antigen encoding loci and microsatellites (AIMS). These AIMS will test our SIDMI hypothesis. If resistance is exposure related, results in long-lasting antibody responses to conserved vaccine candidate antigens and is not limited to 1-2 of the >13 genotypes in the region, it will suggest that a potential mechanism of SIDMI is effective immune responses to more conserved antigens. If the resistance is specific to genotype, it will elucidate the diversity that must be considered in vaccines. PUBLIC HEALTH: The lack of an effective malaria vaccine and sustainable prevention results in >2 million deaths and 300 million severe infections yearly. The prospects for a malaria vaccine are contingent upon understanding natural malaria immunity. This study will provide this breakthrough and give a model for the increasing emergence of malaria into new geographic regions. [unreadable] [unreadable]